Development and evaluation of cell therapy strategies for Alzheimer's disease.

阿尔茨海默病细胞治疗策略的开发和评估。

• 批准号: 10524288
• 负责人: Ksenia V. Kastanenka
• 金额: $ 44.57万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10524288
• 关键词: APP-PS1; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid beta-Protein; Amyloid deposition; Amyloidosis; Animal Model; Automobile Driving; Behavior assessment; Brain; Calcium; Cell Death; Cell Survival; Cell Therapy; Cell Transplantation; Clinical Trials; Cognition; Data; Dementia; Deposition; Development; Disease; Disease Progression; Embryonic Stem Cell Transplantation; Etiology; Evaluation; Exhibits; Frequencies; Functional disorder; GABA Receptor; Ganglia; Harvest; Health; Homeostasis; Impaired cognition; Impairment; Interneurons; Medial; Memory; Memory impairment; Methodology; Monitor; Mus; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Patients; Positioning Attribute; Property; Publishing; Recovery; Reporting; Research; Senile Plaques; Sleep; Testing; Thalamic structure; Therapeutic; Time; Translating; Transplantation; Work; behavior measurement; efficacy evaluation; embryonic stem cell; experience; extracellular; falls; fetal; in vivo calcium imaging; innovation; memory consolidation; mouse model; multiphoton microscopy; neocortical; nervous system disorder; neuron loss; neuronal circuitry; non rapid eye movement; novel; novel therapeutic intervention; optogenetics; preservation; progenitor; programs; restoration; sensor; stem cell therapy; stem cells; voltage

Summary Alzheimer’s disease (AD) is the major cause of dementia. Brain circuit dysfunctions underlie the memory impairments of Alzheimer’s patients. Yet therapeutic approaches pursued in clinical trials failed to target circuits directly. Currently there is no cure. Neuronal activity disruptions have been described as contributing factors to the disease etiology and its progression. Anomalies in sleep-dependent brain rhythms, specifically slow oscillations important for consolidation of memories during deep NREM sleep, have been reported in Alzheimer’s patients. Converging evidence suggests that disruptions in slow oscillations are not simply symptomatic of the disease but facilitate Alzheimer’s progression and might contribute to dementia. Therefore, it is necessary to develop therapeutic strategies targeting restoration of circuit function, such as slow wave activity, to restore cognitive impairments associated with sleep-dependent memory dysfunction. Stem cell-based therapies hold promise for a number of neurological disorders including Alzheimer’s disease. Since deficits in inhibitory tone underly slow oscillation disruptions, restoration of inhibitory tone through transplantation of inhibitory interneuron progenitors might restore circuit function and slow Alzheimer’s progression. Thus, isolation of MGE-derived interneuron progenitors and their transplantation into an animal model of amyloidosis will be performed. We will systematically evaluate whether stem cell therapy restores slow wave activity, slows neuropathophysiology and rescues sleep as well as memory impairments. We propose to employ state-of-the-art methodology including widefield and multiphoton microscopy to monitor circuit function as well as optogenetics to control neuronal activity with high temporal precision. Thus, as a result of this work we will develop and evaluate the efficacy of stem cell therapy for the treatment of Alzheimer’s disease in a mouse model of amyloidosis, thus opening the possibility of translating cell therapy as a cure to slow AD progression in patients as part of a novel therapeutic approach.

概括 阿尔茨海默病（AD）是导致痴呆症的主要原因，大脑回路功能障碍是记忆障碍的基础。 然而，临床试验中所采用的治疗方法未能针对阿尔茨海默病患者的损伤。 目前还没有直接治愈方法，神经元活动中断被认为是造成这种情况的原因。 影响疾病病因及其进展的因素，特别是睡眠依赖性脑节律异常。 慢振荡对于深度 NREM 睡眠期间记忆的巩固非常重要，已在 阿尔茨海默氏症患者的证据表明，缓慢振荡的破坏不仅仅是如此。 是该疾病的症状，但会促进阿尔茨海默病的进展，并可能导致痴呆。 有必要制定针对恢复回路功能的治疗策略，例如慢波 活动，以恢复与睡眠依赖性记忆功能障碍相关的认知障碍。 基于干细胞的疗法有望治疗包括阿尔茨海默病在内的许多神经系统疾病。 由于抑制音调的缺陷导致缓慢的振荡中断，因此通过以下方式恢复抑制音调： 抑制性中间神经元祖细胞移植可能会恢复回路功能并减缓阿尔茨海默病 因此，分离 MGE 进展衍生的中间神经元祖细胞并将其移植到动物体内 我们将进行淀粉样变性模型，系统评估干细胞治疗是否可以恢复。 慢波活动，减缓神经病理生理学并挽救睡眠和记忆障碍。 建议采用最先进的方法，包括宽场和多光子显微镜来监测 电路功能以及光遗传学以高时间精度控制神经活动。 根据这项工作的结果，我们将开发和评估干细胞疗法治疗以下疾病的功效 淀粉样变性小鼠模型中的阿尔茨海默病，从而开启了将细胞疗法转化为 作为一种新型治疗方法的一部分，一种减缓 AD 进展的疗法。